The present invention relates to a novel process for the manufacture of (all-rac.)-xcex1-tocopherol by the acid-catalyzed condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent. (All-rac.)-xcex1-tocopherol, (xe2x80x9cd,l-xcex1-tocopherolxe2x80x9d) is a diastereoisomeric mixture of 2,5,7,8-tetramethyl-2-(4xe2x80x2,8xe2x80x2,12xe2x80x2-trimethyl-tridecyl)-6-chromanol (xcex1-tocopherol), which is the most active and most industrially important member of the vitamin E group.
Many processes for the manufacture of d,l-xcex1-tocopherol by the condensation of TMHQ with IP or PH in the presence of a catalyst or catalyst system and in a solvent or solvent system are described in the literature. These processes go back to the work of Karrer et al., Bergel et al., and Smith et al. (see Helv. Chim. Acta 21, 520 et seq. (1938), Nature 142, 36 et seq. (1938) and, respectively, Science 88, 37 et seq. (1938) and J. Am. Chem. Soc. 61, 2615 et seq. (1939)). While Karrer et al. carried out the synthesis of d,l-xcex1-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (ZnCl2; a Lewis acid), Bergel et al. and Smith et al. used TMHQ and PH as starting materials. In the following years mainly modifications, e.g. alternative solvents and Lewis acids, were developed. From the work of Karrer et al. a technically interesting process for the manufacture of d,l-xcex1-tocopherol which was based on the condensation of TMHQ with IP in the presence of the catalyst system ZnCl2/hydrochloric acid (HCl) (Karrer et al., U.S. Pat. No. 2,411,969) was developed in 1941. Later publications, e.g. Japanese Patent Publications (Kokai) 54380/1985, 64977/1985 and 226979/1987 (Chemical Abstracts (C.A.) 103, 123731s (1985), C.A. 103, 104799d (1985) and, respectively, C.A. 110, 39217r (1989)), describe this condensation in the presence of zinc and/or ZnCl2 and a Bronsted (protonic) acid, such as a hydrohalic acid, e.g. HCl, trichloroacetic acid, acetic acid and the like, especially ZnCl2/HCl, as the catalyst system. The disadvantages of these and further published processes featuring ZnCl2 in combination with a Bronsted acid are the corrosive properties of the acids and the contamination of the waste water with zinc ions as a result of the large amount of ZnCl2 required for the catalysis.
The manufacture of d,l-(xcex1-tocopherol by the reaction of TMHQ with phytyl chloride, PH or IP in the presence of boron trifluoride (BF3) or its etherate (BF3.Et2O) is described in German Patents 960720 and 1015446 and Nelan, U.S. Pat. No. 3,444,213. However, BF3 also has corrosive properties.
Also, the condensation of TMHQ with IP or PH in the presence of a Lewis acid, e.g. ZnCl2, BF3 or aluminum trichloride (AlCl3), a strong acid, e.g. HCl, and an amine salt as the catalyst system is described in European Patent Publication (EP) 100471. In an earlier patent publication, DOS 2606830, the IP or PH is pretreated with ammonia or an amine before the condensation with TMHQ in the presence of ZnCl2 and an acid is effected. In both cases corrosion problems occur.
A further interesting method for the manufacture of d,l-xcex1-tocopherol from TMHQ and IP used an isolated TMHQ-BF3 or -AlCl3 complex and a solvent mixture featuring a nitro compound (DOS 1909164). This process avoids to a large extent the formation of undesired by-products because it involves mild reaction conditions. The yield of d,l-xcex1-tocopherol, based on IP and the use of the solvent mixture methylene chloride/nitro-methane, is given as 77%. However, the use of such a solvent mixture is disadvantageous.
The manufacture of d,l-xcex1-tocopherol by the condensation of TMHQ with IP using cation exchange resin complexes of metal ions (Zn2+, Sn2+ and Sn4+) is disclosed in Bull. Chem. Soc. Japan 50, 2477-2478 (1977). Among other disadvantages, it gives the product in unsatisfactory yields.
The use of macroreticular ion exchangers, e.g. Amberlyst(copyright) 15, as the catalyst for the condensation of TMHQ with IP is described in Moroe et al., U.S. Pat. No. 3,459,773. However, the d,l-xcex1-tocopherol is not produced in satisfactory purity.
EP 603695 describes the manufacture of d,l-xcex1-tocopherol in liquid or supercritical carbon dioxide by the condensation of TMHQ with IP or PH in the presence of acidic catalysts, such as ZnCl2/HCl and ion exchangers. The reported yields are unsatisfactory.
The condensation in the presence of a catalyst system which consists of iron(II) chloride, metallic iron and HCl gas or aqueous solution is described in DOS 2160103 and Heinrich et al., U.S. Pat. No. 3,789,086. The formation of less by-products is advantageous compared with the aforementioned process using ZnCl2/HCl. However, corrosion problems and chloride contamination are disadvantageous.
An interesting alternative for the condensation of TMHQ with IP to d,l-xcex1-tocopherol uses trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although in this process the avoidance of HCl is achieved, the catalyst is expensive.
The use of the heteropoly acid 12-tungstophosphoric or 12-tungstosilicic acid as the catalyst for the condensation of TMHQ with IP was described for the first time in React. Kinet. Catal. Lett. 47 (1), 59-64 (1992). d,l-xcex1-Tocopherol could be obtained, using various solvents, in about 90% yield.
A further process described in the literature (EP 658552; Bull. Chem. Soc. Japan 68, 3569-3571 (1995)) for the synthesis of d,l-xcex1-tocopherol is based on the use of a scandium, yttrium or lanthanide fluorosulphonate, nitrate or sulphate, e.g. scandium trifluoromethanesulphonate, as the catalyst for the condensation. With up to about 10% excess of IP this process gives yields up to 98%.
The use of ion-exchanged bentonite, montmorillonite or saponite through treatment with e.g. scandium chloride and other metal salts (yttrium, lanthanum, etc.) as the catalyst for the condensation of TMHQ with IP or PH has as a disadvantage the need for a large amount of catalyst (EP 677520; Bull. Chem. Soc. Japan 69, 137-139 (1996)).
According to the Examples of EP 694 541, the condensation of TMHQ with IP to xcex1-tocopherol can be achieved in high yields and with a high product purity when such solvents as carbonate esters, fatty acid esters and certain mixed solvent systems are employed, the exemplified catalysis being effected by ZnCl2/HCl. Disadvantages in this process are, in addition to the contamination of the waste water by zinc ions, the usual large xe2x80x9ccatalyst amountxe2x80x9d of ZnCl2 used.
According to WO 97/28151, the acid-catalyzed condensation of TMHQ with IP can be performed using a cyclic carbonate or xcex1-lactone as the solvent. The preferred catalyst is a mixture of orthoboric acid and oxalic, tartaric or citric acid, or boron trifluoride etherate.
WO 98/21197 describes the manufacture of d,l-xcex1-tocopherol from TMHQ and IP using bis(trifluoromethylsulphonyl)amine or a metal salt thereof optionally together with a strong Bronsted acid, as catalyst in such types of aprotic solvents as aliphatic and cyclic ketones or esters, and aromatic hydrocarbons.
From the forgoing review it is evident that most of the previously known processes have considerable disadvantages. Thus, corrosion problems occur in all processes in which such acid catalysts as boron trifluoride are used. Toxicity problems with the boron trifluoride adducts also occur, and when iron or zinc is used there is a contamination of the waste water with the metal ions which is today no longer acceptable. In some processes the formation of undesired by-products, e.g. phytyltoluene and chlorophytols, is an especially serious problem.
An object of the present invention is to provide a process for the manufacture of (all-rac.)-xcex1-tocopherol by the condensation of trimethylhydroquinone with isophytol or phytol in the presence of a catalyst and in a solvent which does not have the disadvantages of previously known procedures. In this respect, it is necessary that the catalyst used has no, or at least a much reduced, corrosive action, is non-toxic, does not contaminate the environment and catalyzes the desired reaction as selectively as possible and in high yields. Furthermore, the catalyst should display its activity in small, catalytic amounts and should be readily separable and reusable several times.
Another object of the invention is a method of making (all-rac.)-xcex1-tocopherol. This method includes: reacting trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in an organic solvent and in the presence of a tris(perfluoroalkanesulphonyl)methane, a tris(pentafluorobenzenesulphonyl)methane, a metal tris(perfluoroalkanesulphonyl)methide, or a metal tris(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R1SO2)3C]x R2 xe2x80x83xe2x80x83I 
wherein
R1 is a perfluoroalkyl group CnF2n+1 or pentafluorophenyl,
R2 is a proton or a metal cation selected from the group consisting of boron, magnesium, aluminium, silicon, scandium, titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium, neodymium, europium, dysprosium, ytterbium, hafnium, platinum, and gold,
n is an integer from 1 to 10, and
x is the corresponding valency of the proton (1) or metal cation (1, 2, 3, or 4);
and isolating the (all-rac.)-xcex1-tocopherol.
Another embodiment of the invention is an acid-catalyzed process for producing (all-rac.)-xcex1-tocopherol. This process includes forming a reaction mixture comprising trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH), an organic solvent, and a tris(perfluoroalkanesulphonyl)methane, a tris(pentafluorobenzenesulphonyl)methane, a metal tris(perfluoroalkanesulphonyl)methide, or a metal tris(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R1SO2)3C]x R2 xe2x80x83xe2x80x83I 
wherein
R1 is a perfluoroalkyl group CnF2n+1 or pentafluorophenyl,
R2 is a proton or a metal cation selected from the group consisting of boron, magnesium, aluminium, silicon, scandium, titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium, neodymium, europium, dysprosium, ytterbium, hafnium, platinum, and gold,
n is an integer from 1 to 10, and
x is the corresponding valency of the proton (1) or metal cation (1,2,3 or 4);
and isolating the (all-rac.)-xcex1-tocopherol.
A further embodiment of the invention is a reaction mixture containing:
(a) trimethylhydroquinone (TMHQ),
(b) isophytol (IP) or phytol (PH) in an organic solvent, and
(c) a tris(perfluoroalkanesulphonyl)methane, a tris(pentafluorobenzenesulphonyl)methane, a metal tris(perfluoroalkanesulphonyl)methide, or a metal tris-(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R1SO2)3C]x R2 xe2x80x83xe2x80x83I 
wherein
R1 is a perfluoroalkyl group CnF2n+1 or pentafluorophenyl,
R2 is a proton or a metal cation selected from the group consisting of boron, magnesium, aluminium, silicon, scandium, titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium, neodymium, europium, dysprosium, ytterbium, hafnium, platinum, and gold,
n is an integer from 1 to 10, and
x is the corresponding valency of the proton (1) or metal cation (1,2,3 or 4).
In this reaction mixture, (all-rac.)-xcex1-tocopherol is formed by an acid-catalyzed condensation.
The objects of the present invention are achieved by carrying out the condensation of trimethylhydroquinone with isophytol or phytol in the presence of a so-called CH-acidic compound or a metal salt thereof, which is more particularly a tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methane or a metal tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methide, in an organic solvent.
The condensation itself is represented in the following Reaction Scheme, showing the reaction with IP only. 
Accordingly, the process in accordance with the invention for the manufacture of (all-rac.)-xcex1-tocopherol by the catalyzed condensation of trimethylhydroquinone with isophytol or phytol, is characterized by carrying out the condensation in the presence of a tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methane or a metal tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methide, of the general formula
[(R1SO2)3C]x R2 xe2x80x83xe2x80x83I 
wherein
R1 is a perfluoroalkyl group CnF2n+1 or pentafluorophenyl,
R2 is a proton or a metal cation selected from the group consisting of boron, magnesium, aluminium, silicon, scandium, titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin, lanthanum, cerium, praseodymium, neodymium, europium, dysprosium, ytterbium, hafnium, platinum and gold, each in the cationic form,
n is an integer from 1 to 10 and
x is the corresponding valency of the proton (1) or metal cation (1,2,3 or 4), as the catalyst in an organic solvent.
Some of the CH-acidic compounds and their metal salts of formula I are known compounds. Thus, in Inorg. Chem. 27, 2135-2137 (1988) K. Seppelt and L. Turowsky describe for the first time the preparation of tris(trifluoromethanesulphonyl)methane, (CF3SO2)3CH, and of four salts thereof, viz. the potassium, rubidium, silver and cesium salts. The lithium and further metal salts of (CF3SO2)3CH and other tris(perfluoroalkanesulphonyl)methides and their preparation are described in Dominey, U.S. Pat. No. 5,273,840. Also developing the original work of Seppelt and Turowsky, F. J. Waller et al. describe in J. Org. Chem. 64, 2910-2913 (1999) the further preparation of (CF3SO2)3CH and its cesium salt, and also the preparation of the corresponding scandium and ytterbium salts. In Synlett 1999, No. 12, 1990-1992, J. Nishikido et al. describe the preparation of scandium, yttrium and, in general, lanthanide (III) tris(perfluorobutanesulphonyl)methide complexes. Further literature concerning the preparation of these and further metal tris(perfluoroalkanesulphonyl)methides includes Lamanna et al., U.S. Pat. No. 5,554,664 and the many references mentioned in this and in other aforementioned publications.
The tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methanes or metal salts thereof embraced by formula I and used as the catalysts in the process of the present invention can be produced according to such published methods, or in the case of those methanes or metal salts thereof which may still not be known, according to analogous methods.
In the case of the metal tris(perfluoroalkanesulphonyl or pentafluorobenzenesulphonyl)methides (the metal salts), this catalyst can be used together with a strong Bronsted acid as a co-catalyst in the process of the present invention. The Bronsted acid present in such a catalyst system can be an inorganic or organic acid, examples of which are sulfuric acid, phosphoric acid, and p-toluenesulphonic acid. In the case of using a lithium salt as the catalyst of formula I (R2 being the lithium cation), the use of a Bronsted acid as a co-catalyst is particularly preferred.
Solvents which can be used in the present invention are polar or non-polar organic solvents. Suitable classes of polar solvents include aliphatic and cyclic ketones, e.g. isobutyl methyl ketone and diethyl ketone and, respectively, cyclopentanone and isophorone; and aliphatic and cyclic esters, e.g. ethyl acetate and isopropyl acetate, and, respectively, xcex3-butyrolactone, ethylene carbonate and propylene carbonate. Suitable classes of non-polar solvents include aliphatic hydrocarbons, e.g. hexane, heptane and octane, and aromatic hydrocarbons, e.g. benzene, toluene and the xylenes. The condensation can be effected in a single solvent phase, e.g. in toluene alone as the solvent, or in a biphasic solvent system, e.g. in ethylene carbonate and hexane.
The method is conveniently effected at temperatures from about 60xc2x0 C. to about 150xc2x0 C., preferably from about 100xc2x0 C. to about 120xc2x0 C.
Furthermore, the molar ratio of trimethylhydroquinone to isophytol/phytol present in the reaction mixture is from about 1.3:1 to about 2.5:1, preferably from about 1.5:1 to about 2.2:1, such as for example about 2:1.
The amount of catalyst of formula I used is such that the molar ratio of catalyst to the educt (trimethylhydroquinone or isophytol/phytol) which is in the lesser molar amount (generally the isophytol or phytol) is from about 0.1:100 to about 2:100, i.e. is from about 0.1 mole % to about 2 mole %.
Conveniently about 10-100 ml, preferably about 30-60 ml, of organic solvent are used per 10 mmol of isophytol or phytol, whichever is employed.
If the process reaction is carried out in a biphasic solvent system, especially one consisting of a polar solvent, e.g. a cyclic carbonate such as ethylene or propylene carbonate, and a non-polar solvent, e.g. an aliphatic hydrocarbon such as hexane, then the volume ratio of the non-polar solvent to the polar solvent is from about 0.3:1 to about 5:1, preferably from about 1:1 to about 3:2.
Moreover, the process reaction may be carried out under an inert gas atmosphere, preferably gaseous nitrogen or argon.
The reaction generally lasts for about 0.2-20 hours, preferably about 0.5-1 hour.
The method in accordance with the invention can be carried out batchwise or continuously. For example, isophytol or phytol may be added, as such or in solution, portionwise to a suspension or solution of the trimethylhydroquinone and the catalyst. The rate at which the isophytol or phytol is added is not critical. Conveniently, isophytol/phytol is added continuously over a period 0.5 to 5 hours. After completion of the isophytol/phytol addition and an appropriate subsequent reaction period the working-up is effected by procedures conventionally used in organic chemistry.
If desired, the obtained (all-rac.)-xcex1-tocopherol can be converted into its acetate, succinate, poly(oxyethylene)succinate, nicotinate and further known application forms by standard procedures (See, for example, the 5th Edition of Ullmann""s Encyclopedia of Industrial Chemistry, Vol. A 27, pages 484-485 (VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996)).
The process in accordance with the invention enables the catalyst used to be separated readily and to be reused several times.
Advantages in the use of the catalyst in the process in accordance with the invention are, in addition to high yields of (all-rac.)-xcex1-tocopherol, the avoidance of corrosion, the avoidance of waste water contamination with heavy metal ions, high selectivity, and easy isolation of the (all-rac.)-xcex1-tocopherol product from the mixture after reaction.
The following examples are provided to further illustrate the process of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.